Modakafusp alfa in Relapsed/Refractory Multiple Myeloma: Insights from a Phase 2 Randomized Dose Optimization Study

Study Background and Disease Burden

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells in the bone marrow, leading to bone destruction, anemia, renal dysfunction, and immunodeficiency. Despite recent therapeutic advances including proteasome inhibitors, immunomodulatory agents, monoclonal antibodies targeting CD38 or B-cell maturation antigen (BCMA), and CAR-T cell therapies, relapsed/refractory multiple myeloma (RRMM) remains incurable with limited treatment options for heavily pretreated patients. The emergence of triple-class refractory disease—defined as resistance to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies—poses a significant clinical challenge. Novel therapeutic agents with unique mechanisms of action targeting resistant myeloma cells are urgently needed to extend progression-free survival (PFS) and improve response rates in this difficult-to-treat population.

Modakafusp alfa is a first-in-class immunocytokine that directs interferon alfa to CD38-expressing cells, combining targeted immunomodulation with direct antitumor effects. By selectively delivering interferon alfa to the myeloma cells, modakafusp alfa aims to enhance antimyeloma immune responses while minimizing systemic interferon-associated toxicity. Early phase 1/2 data showed promising overall response rates (ORR) with two potential therapeutic doses identified. This phase 2 dose optimization study (NCT03215030) further evaluates efficacy and safety in a large cohort of heavily pretreated, triple-class refractory patients, many of whom had prior exposure to BCMA-directed therapies.